Characterization and Diagnosis of Alzheimer's Disease Using mRNA Biomarkers
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ABSTRACT Alzheimer’s disease (AD) is the most common progressive neurodegenerative disease; it is the leading cause of dementia, disability, and death in aging populations. Currently, AD and AD-related dementia (ADRD) affect at least 50 million people globally; it is forecast to increase to 152 million by 2050. Currently, the diagnosis of AD is complicated and requires multiple tests involving neuropsychological assessments, neuroimaging (MRI, PET), and analysis of cerebrospinal fluid (CSF) biomarkers, including amyloid β 42 (Aβ42), Tau, and phosphorylated Tau (pTau), using immunohistochemistry and enzyme-linked immunosorbent assay (ELISA). These screening techniques are often time-consuming, expensive, and invasive, limiting patient access and making early disease detection difficult. We will develop a portable diagnostic system to sense circulating miRNA biomarkers from patient plasma for AD to remove these barriers and improve patient outcomes. Our proposed system, referred to as Alzheimer’s detection via miRNA Evaluation (ADmiRE), integrates two unique but proven technologies: (1) an amplification- free miRNA biosensing modality called the 'inverse Molecular Sentinel' (iMS) and (2) a unique chip platform based on plasmonic "super-bright" bimetallic nanostars for ultrasensitive and reproducible surface-enhanced Raman scattering (SERS) detection. iMS probes will be designed for miRNA biomarkers identified via next- generation smRNA analysis of plasma from early AD patients and healthy age-matched controls. For analytical validation, plasma samples from AD patients and healthy age-matched controls will be assayed in our system, with the results compared to those obtained with the traditional RT-PCR method. The proposed non-invasive, simple, and rapid integrated system will enable an amplification-free ("sample-to-answer") diagnosis without the need for RT-PCR. The ADmiRE technology, allowing the diagnostic result to be rendered in the outpatient setting, will identify ADs and empower clinicians to help improve patient outcomes. The project’s aims are the following: (1) Evaluate and optimize an iMS nanoprobe panel to detect and characterize AD; (2) Design and develop the ADmiRE diagnostic platform; and (3) Technical evaluation of the ADmiRE system for identifying AD and ADRDs directly from patient plasma samples. The potential Impact of the ADmiRE system is vast and significant. It will serve as a foundation for a rapid, plasma-based testing platform capable of identifying AD early, eliminating the need for laboratory-based assays —a critical monitoring tool currently unavailable to clinicians. We are promoting early detection of AD because it has been shown that early disease intervention can significantly improve patient outcomes. Completing this project will allow us to establish an iMS nanoprobe panel for AD identification, fabricate the ADmiRE system, and proceed to the clinical testing of patient plasma samples.
